WO2016140237A1 - Composition for improving or preventing nonalcoholic fatty liver - Google Patents

Composition for improving or preventing nonalcoholic fatty liver Download PDF

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WO2016140237A1
WO2016140237A1 PCT/JP2016/056341 JP2016056341W WO2016140237A1 WO 2016140237 A1 WO2016140237 A1 WO 2016140237A1 JP 2016056341 W JP2016056341 W JP 2016056341W WO 2016140237 A1 WO2016140237 A1 WO 2016140237A1
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liver
fatty liver
disease
present
glutathione
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PCT/JP2016/056341
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French (fr)
Japanese (ja)
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貴臣 結束
中島　淳
圭雄 角田
江口　有一郎
晋 斉藤
勇亮 佐内
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興人ライフサイエンス株式会社
公立大学法人横浜市立大学
京都府公立大学法人
国立大学法人佐賀大学
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Priority to BR112017018882A priority Critical patent/BR112017018882A2/en
Priority to EP16758930.8A priority patent/EP3266461A4/en
Priority to CN201680013232.8A priority patent/CN107405376A/en
Priority to US15/555,901 priority patent/US20180050078A1/en
Priority to CA2978251A priority patent/CA2978251C/en
Priority to RU2017134036A priority patent/RU2746091C2/en
Priority to AU2016226906A priority patent/AU2016226906B2/en
Priority to JP2017503669A priority patent/JP6890536B2/en
Application filed by 興人ライフサイエンス株式会社, 公立大学法人横浜市立大学, 京都府公立大学法人, 国立大学法人佐賀大学 filed Critical 興人ライフサイエンス株式会社
Priority to MX2017011363A priority patent/MX2017011363A/en
Publication of WO2016140237A1 publication Critical patent/WO2016140237A1/en
Priority to PH12017550090A priority patent/PH12017550090B1/en
Priority to US16/232,747 priority patent/US20190125822A1/en
Priority to US16/889,367 priority patent/US11207371B2/en
Priority to US17/530,609 priority patent/US11771735B2/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/03—Peptides having up to 20 amino acids in an undefined or only partially defined sequence; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/06—Tripeptides
    • A61K38/063—Glutathione
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/06—Tripeptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics

Abstract

[Problem] The present invention addresses the problem of providing a composition for preventing or improving the deposition of fat in the liver, irrespective of an alcohol intake history of a level such that alcohol intake is not the cause of liver disease. [Solution] The inventors discovered that glutathione has an effect for preventing or improving fat deposition in the liver that is not caused by alcohol, thereby perfecting the present invention. In particular, the present invention is effective when nonalcoholic fatty liver disease is not treated early or when no treatment is conducted for another disease.

Description

非アルコール性脂肪肝改善又は予防組成物Non-alcoholic fatty liver improving or preventing composition
　本発明は、アルコール摂取が肝臓疾患の原因にならない程度のアルコール摂取歴にも関わらず、肝臓に脂肪が沈着していく、非アルコール性脂肪肝を予防、改善する組成物に関する。 The present invention relates to a composition for preventing and improving non-alcoholic fatty liver, in which fat is deposited in the liver despite the history of alcohol intake to the extent that alcohol intake does not cause liver disease.
  生活習慣病として、糖尿病、脂肪肝、ガン、心疾患などの増加が問題となっている。アルコール摂取が肝臓疾患の原因にならない程度のアルコール摂取歴にも関わらず、肝臓に脂肪が沈着して肝障害を引き起こすことがある。肥満、糖尿病、高脂血症などが原因とされているが、発症にかかわる因子は多岐にわたり確立した治療法はない。このような非アルコール性脂肪肝疾患（nonalcoholic fatty liver disease（NAFLD））は、非アルコール性脂肪肝炎（nonalcoholic steatohepatitis(NASH）)、肝硬変、肝臓癌に病態が進行していく場合がある。非アルコール性脂肪性肝疾患ではインスリン抵抗性、肥満、糖尿病及び高脂血症を伴っていることが多い。通常、非アルコール性脂肪肝疾患は、運動・食事療法が行われている。また、非アルコール性脂肪性肝疾患には、運動・食事療法等以外の薬剤での治療や栄養補助食品などを利用した食事療法が求められている。さらに、非アルコール性脂肪肝炎においては、肝硬変・肝細胞癌へと進展する可能性があることから、より積極的な治療等が必要である。 増 加 Increased diabetes, fatty liver, cancer, heart disease, etc. as lifestyle diseases. Despite a history of alcohol consumption to the extent that alcohol consumption does not cause liver disease, fat can deposit in the liver and cause liver damage. Although it is caused by obesity, diabetes, hyperlipidemia, etc., there are no widely established treatment methods for the factors involved in the onset. Such nonalcoholic fatty liver disease (NAFLD) may progress to nonalcoholic steatohepatitis (NASH), cirrhosis, and liver cancer. Nonalcoholic fatty liver disease is often accompanied by insulin resistance, obesity, diabetes and hyperlipidemia. Usually, exercise / diet therapy is performed for non-alcoholic fatty liver disease. In addition, non-alcoholic fatty liver disease is required to be treated with drugs other than exercise / dietary therapy, etc., or dietary therapy using dietary supplements. Furthermore, in non-alcoholic steatohepatitis, since there is a possibility of progressing to cirrhosis / hepatocellular carcinoma, more aggressive treatment or the like is necessary.
　非アルコール性脂肪性疾患は、糖尿病などの治療を行っていることがあるため、合併症の治療を阻害しない非アルコール性脂肪肝疾患の改善をする必要もある。
　そのため、効果が高く、副作用の心配がなく、摂取が容易であり、長期間服用ができる非アルコール性脂肪性肝疾患の治療効果のある機能性食品、サプリメントなども求められていた。 Since non-alcoholic fatty diseases may be treated for diabetes or the like, it is also necessary to improve non-alcoholic fatty liver diseases that do not inhibit the treatment of complications.
Therefore, there has been a demand for functional foods and supplements that are highly effective, have no worries about side effects, can be taken easily, and can be taken for a long period of time, and have a therapeutic effect on nonalcoholic fatty liver disease.
  一方、グルタチオンは、システイン、グルタミン酸、グリシンといったアミノ酸からなるトリペプチドであり、肝臓の解毒作用改善薬として知られている。
しかし、グルタチオンが非アルコール性脂肪性肝疾患に有効であることは、知られていなかった。 On the other hand, glutathione is a tripeptide composed of amino acids such as cysteine, glutamic acid, and glycine, and is known as a drug for improving the detoxification of the liver.
However, it has not been known that glutathione is effective for nonalcoholic fatty liver disease.
国際公開WO2009/096455International Publication WO2009 / 096455 特開2006-199708JP 2006-199708
　本願は、アルコール摂取が肝臓疾患の原因にならない程度のアルコール摂取歴にも関わらず、肝臓に脂肪が沈着していくことを予防、改善する組成物を提供することを課題とする。 This application makes it a subject to provide the composition which prevents and improves fat deposition to the liver, despite the alcohol intake history that alcohol intake does not cause liver disease.
本願発明者らは、グルタチオンに、アルコールが原因とならない肝臓への脂肪沈着を予防、改善する効果を有することを見出し、本発明を完成させた。 The inventors of the present application have found that glutathione has an effect of preventing and improving fat deposition in the liver not caused by alcohol, and completed the present invention.
本発明は、以下の通りである。
（１）グルタチオンを有効成分として含有する非アルコール性脂肪肝疾患の改善用組成物、
（２）グルタチオンを有効成分として含有する非アルコール性脂肪肝疾患の予防用組成物、
（３）非アルコール性脂肪肝疾患が、非アルコール性脂肪肝のみを発症している疾患である（１）又は（２）の組成物、
（４）非アルコール性脂肪肝疾患が、糖尿病を併発していない疾患である（１）又は（２）の組成物、
（５）非アルコール性脂肪肝疾患が、肝硬度の低い疾患である（１）又は（２）の組成物。
（６）非アルコール性脂肪肝疾患が、糖化ヘモグロビン（ＨｂＡ１ｃ）濃度が６．５％以下の疾患である（１）又は（２）の組成物、 The present invention is as follows.
(1) A composition for improving non-alcoholic fatty liver disease containing glutathione as an active ingredient,
(2) A composition for preventing non-alcoholic fatty liver disease containing glutathione as an active ingredient,
(3) The composition according to (1) or (2), wherein the non-alcoholic fatty liver disease is a disease that develops only non-alcoholic fatty liver disease,
(4) The composition according to (1) or (2), wherein the non-alcoholic fatty liver disease is a disease not accompanied by diabetes,
(5) The composition according to (1) or (2), wherein the non-alcoholic fatty liver disease is a disease having low liver hardness.
(6) The composition according to (1) or (2), wherein the non-alcoholic fatty liver disease is a disease having a glycated hemoglobin (HbA1c) concentration of 6.5% or less,
本発明の組成物は、非アルコール性脂肪性肝に対して、肝臓に蓄積した脂肪を低減して脂肪肝を改善するために有効に用いることができ、さらに肝障害への進展を抑制することができる。このため、本発明の肝臓脂肪蓄積抑制剤、および脂肪肝改善剤は、上述の作用に基づいて、さらに肝硬変、肝炎及び肝癌への進展を予防又は改善する作用を有する。 The composition of the present invention can be effectively used to improve fatty liver by reducing fat accumulated in the liver against non-alcoholic fatty liver, and further suppress the progression to liver damage Can do. For this reason, the liver fat accumulation inhibitor and the fatty liver improving agent of the present invention have the effect of preventing or improving the progression to cirrhosis, hepatitis and liver cancer based on the above-described effects.
本発明の組成物は、非アルコール性脂肪肝の初期の段階、特に高血圧、高脂血症又は耐糖能異常などの代謝異常のない又は軽い病態を有する患者、肝硬度の低い患者、脂肪肝以外の疾患が認められない患者に対して、有効に用いることができる。前記のような場合であれば、食事、運動療法等が有効でない疾患であっても本願発明は、有効である。 The composition of the present invention is used in the early stage of nonalcoholic fatty liver, particularly in patients with no or mild metabolic conditions such as hypertension, hyperlipidemia or impaired glucose tolerance, patients with low liver hardness, non-fatty liver It can be used effectively for patients who do not have any other disease. In the case as described above, the present invention is effective even for diseases in which diet, exercise therapy or the like is not effective.
 以下、本発明を詳細に説明する。
　本願発明において、非アルコール性脂肪性肝疾患（nonalcoholic fatty liver disease（NAFLD））とは、アルコール摂取が、肝臓疾患の原因にならない程度のアルコール摂取歴にも関わらず、肝細胞に脂肪が異常蓄積することに起因して肝障害をきたす疾患及び肝障害をきたすおそれがある状態を意味し、非アルコール性単純性脂肪肝、非アルコール性脂肪肝炎を含む。一般的には、1日あたりのアルコール摂取量が２０ｇ以下にもかかわらず肝細胞に脂肪が沈着して肝障害を引き起こす病態を示す。 Hereinafter, the present invention will be described in detail.
In the present invention, nonalcoholic fatty liver disease (NAFLD) is an abnormal accumulation of fat in hepatocytes despite alcohol consumption to the extent that alcohol intake does not cause liver disease. It means a disease that causes liver damage due to the cause and a state that may cause liver damage, and includes nonalcoholic simple fatty liver and nonalcoholic steatohepatitis. In general, although the amount of alcohol intake per day is 20 g or less, fat is deposited on hepatocytes and causes a liver disorder.
　本願発明において、非アルコール性脂肪性肝の改善とは、肝機能を悪化させないということである。また急性肝炎、肝不全、慢性肝炎、脂肪肝、肝硬変など疾病の治療効果を指す。具体的には、例えば肝臓の脂肪蓄積防止、又は、肝機能の臨床検査項目となっているＡＬＴ（アラニンアミノトランスフェラーゼ） の上昇抑制又は下降を指している。本願発明において、非アルコール性脂肪性肝炎の予防とは、肝機能の臨床検査項目となっているALTの上昇抑制又は下降を指している。
　 In the present invention, the improvement of nonalcoholic fatty liver means that liver function is not deteriorated. It also refers to the therapeutic effect of diseases such as acute hepatitis, liver failure, chronic hepatitis, fatty liver, cirrhosis. Specifically, for example, it indicates prevention of liver fat accumulation, or suppression or decrease of ALT (alanine aminotransferase), which is a clinical test item for liver function. In the present invention, prevention of non-alcoholic steatohepatitis refers to suppression or decrease of ALT, which is a clinical test item for liver function.
 また、本願発明は、上記の非アルコール性脂肪性肝疾患のうち、脂肪肝のみを発症している場合、糖尿病を発症（併発）していない場合、肝硬度が低い場合、又は肝硬変を発症していない場合に特に有効である。特に、非アルコール性脂肪性肝疾患のみの治療、改善、予防をする場合に有効的である。糖尿病を発症している場合であっても、肝硬度が低い場合、糖尿病治療を行っていない場合は、本発明が有効である。 In addition, the invention of the present application, among the above non-alcoholic fatty liver diseases, develops only fatty liver, does not develop diabetes (concurrent), develops liver cirrhosis, or develops cirrhosis. It is especially effective when not. In particular, it is effective when treating, improving, or preventing only non-alcoholic fatty liver disease. Even in the case of developing diabetes, the present invention is effective when liver hardness is low or when diabetes treatment is not performed.
　本願発明で、非アルコール性脂肪肝のみ発症しているとは、通常の診断において、非アルコール性脂肪肝と診断される脂肪肝のみを発症していることである。一般的には、腹部超音波検査診断や画像診断等で肝臓への脂肪沈着が認められ、脂肪肝の検査項目であるＡＬＴに異常が認められるが、他の検査項目は、正常値又は治療を要さない程度の状態を示す。 In the present invention, the expression of only non-alcoholic fatty liver means that only non-alcoholic fatty liver is diagnosed in normal diagnosis. In general, fat deposition in the liver is observed in abdominal ultrasonography diagnosis or imaging diagnosis, and abnormalities are found in ALT, which is a test item of fatty liver, but other test items are normal values or treatment Indicates a state that is not necessary.
　本願発明で、糖尿病を発症していない患者とは、糖化ヘモグロビン（ＨｂＡ１ｃ）濃度が６．５％以下（ＮＧＳＰ値）の患者をいう。また、糖化ヘモグロビン濃度が６．５％以上であっても、糖尿病の治療を行っていない場合には、本発明は有効である。
　糖化ヘモグロビンは、血液検査により得られるもので、総ヘモグロビン中に占めるＨｂＡ１ｃの割合をいう。 In the present invention, a patient who has not developed diabetes refers to a patient having a glycated hemoglobin (HbA1c) concentration of 6.5% or less (NGSP value). Even if the glycated hemoglobin concentration is 6.5% or more, the present invention is effective when diabetes is not being treated.
Glycated hemoglobin is obtained by a blood test and refers to the proportion of HbA1c in the total hemoglobin.
本願発明は、高血圧又は高脂血症を併発していない場合にも有効である。
ここで、高血圧とは収縮期血圧（最高血圧）が１４０ｍｍＨｇ以上、拡張期血圧（最低血圧）が９０ｍｍＨｇ以上の患者、高脂血症は、血液中の脂質、具体的にはコレステロールや中性脂肪（代表的なものはトリグリセリド）が多いことをいい、一般的には（　１　）　高コレステロール血症（血液中の総コレステロール値：２２０ｍｇ／ｄＬ以上）、（　２　）高ＬＤＬコレステロール血症（血中低比重リポ蛋白（ＬＤＬ）：１４０ｍｇ／ｄＬ以上）　、（３）低ＨＤＬコレステロール血症（血中のＨＤＬ：４０ｍｇ／ｄＬ未満）、（４）高トリグリセリド血症　（血中のトリグリセリドが高い：　１５０ｍｇ／ｄＬ以上）の患者である。本発明においては、高血圧又は高脂血症の疾患の予備軍とよばれる患者も含むとする。 The present invention is also effective when hypertension or hyperlipidemia is not accompanied.
Here, hypertension is a patient whose systolic blood pressure (maximum blood pressure) is 140 mmHg or more, diastolic blood pressure (minimum blood pressure) is 90 mmHg or more, and hyperlipidemia is lipid in blood, specifically cholesterol or neutral fat. (Typical is a triglyceride), generally (1) Hypercholesterolemia (total cholesterol level in blood: 220 mg / dL or more), (2) High LDL cholesterolemia (in blood Low-density lipoprotein (LDL): 140 mg / dL or higher), (3) Low HDL cholesterolemia (HDL in blood: less than 40 mg / dL), (4) Hypertriglyceridemia (high blood triglyceride: 150 mg / DL or more). In the present invention, a patient referred to as a reserve for hypertension or hyperlipidemia is also included.
本願発明では、肝硬度の低い疾患とは、以下のいずれか１つに該当する疾患をいうが、これに限らず、他の診断方法においても、肝硬度が低い疾患であれば、本願発明は有効である。
（１）血清中IV型コラーゲン（Type IV collagen 7S domain）の測定値が、４．５ｎｇ／ｍｌ以下、
（２）非侵襲的検査法としてパルス振動波の組織内伝搬速度を超音波画像解析法により弾性度（ｋＰａ）で測定するｔｒａｎｓｉｅｎｔｅｌａｓｔｏｇｒａｐｈｙを原理としたフィブロスキャン（ＦｌｂｒｏＳｃａｎ；ＥＣＨＯＳＥＮＳ社製）での測定値が、９．０ｋＰａ以下。 In the present invention, a disease with low liver hardness refers to a disease that falls under any one of the following, but is not limited to this, and in other diagnostic methods, the present invention is not limited to a disease with low liver hardness. It is valid.
(1) The measured value of serum type IV collagen 7S domain is 4.5 ng / ml or less,
(2) Measurement value by fibroscan (FlbroScan; manufactured by ECHOSENS Co., Ltd.) based on the principle of transimetry, which measures the propagation velocity of pulse vibration wave in tissue as a non-invasive examination method with the elasticity (kPa) by ultrasonic image analysis. Is 9.0 kPa or less.
　本発明でいうグルタチオンは、還元型グルタチオン若しくは酸化型グルタチオン又はこれらの混合物をいう。還元型グルタチオンとはγ － Ｌ － Ｇ ｌ ｕ － Ｌ － Ｃ ｙ ｓ － Ｇ ｌ ｙ の構造を有するトリペプチドを表し、酸化型グルタチオンとは還元型グルタチオン２ 分子がＳ－Ｓ 結合により結合したものである。グルタチオンの形態は、グルタチオンが有効成分として含有するものであれば何でもよい。 As used herein, glutathione refers to reduced glutathione, oxidized glutathione, or a mixture thereof. Reduced glutathione represents a tripeptide having a structure of γ-L-G l u-L-C y s-G l y, and oxidized glutathione is a combination of reduced glutathione 2 molecules by SS に よ り bond. It is. The form of glutathione may be anything as long as glutathione contains as an active ingredient.
 本発明のグルタチオンは、医薬品又は食品として使用できる方法で取得されれば、特に制限はない。通常は、酵母等の微生物、酵素を用いた合成等により製造される。 The glutathione of the present invention is not particularly limited as long as it is obtained by a method that can be used as a pharmaceutical or a food. Usually, it is produced by microorganisms such as yeast, synthesis using an enzyme, or the like.
 グルタチオンを有効成分として含むものを投与する方法は、特に限定されず、経口投与、静脈内、腹膜内もしくは皮下投与等の非経口投与をあげることができる。具体的には、錠剤、散剤、顆粒剤、丸剤、懸濁剤、乳剤、浸剤・煎剤、カプセル剤、シロップ剤、液剤、エリキシル剤、エキス剤、チンキ剤、流エキス剤等の経口剤、又は注射剤、点滴剤、クリーム剤、坐剤等の非経口剤のいずれでもよい。 There is no particular limitation on the method for administering those containing glutathione as an active ingredient, and examples include oral administration, parenteral administration such as intravenous, intraperitoneal or subcutaneous administration. Specifically, oral preparations such as tablets, powders, granules, pills, suspensions, emulsions, soaking and decoction, capsules, syrups, solutions, elixirs, extracts, tinctures, fluid extracts, Or any of parenteral agents, such as an injection, a drip, a cream, and a suppository, may be sufficient.
　グルタチオンを含有する酵母を経口投与することもできる。グルタチオンを多く含有する酵母としては「ハイチオンコーボＭＧ」（興人ライフサイエンス社製）、グルタチオンを含有する酵母エキスとしては「ハイチオンエキスＹＨ」（興人ライフサイエンス社製）などがある。 Yeast containing glutathione can also be administered orally. Examples of yeasts containing a large amount of glutathione include “Hythion Cobo MG” (manufactured by Kojin Life Sciences), and examples of yeast extracts containing glutathione include “Hythion Extract YH” (manufactured by Kojin Life Sciences).
　本発明の投与量は、前述の機能が発現する量でれば特に限定されない。ヒトに投与する場合の投与量および投与回数は、投与形態、被投与者の年齢、体重等により異なるが、成人一日当り、グルタチオンを通常は５ ０ ｍ ｇ ～ ３ ０ ｇ 、好ましくは１ ０ ０ ｍ ｇ ～ １ ０ｇ、特に好ましくは２ ０ ０ ｍ ｇ ～ ３ ｇ となるように一日一回乃至数回投与する。 The dose of the present invention is not particularly limited as long as it is an amount that exhibits the above-mentioned function. When administered to humans, the dosage and frequency of administration vary depending on the dosage form, age of the recipient, body weight, etc., but glutathione is usually from 5 to m g to 3 0 g, preferably 1 0 0 per day for adults. It is administered once to several times a day so that it becomes m g ˜ 1 0g, particularly preferably 2 0 0 m g to 3 g.
 本発明の組成物は、医薬品だけでなく、機能性食品、栄養補助食品としても摂取可能であり、その場合、前段の摂取量になるよう摂取すればよい。
The composition of the present invention can be ingested not only as a pharmaceutical product but also as a functional food and a nutritional supplement.
(実施例１）
（NASH/NAFLDに対する有効性評価）
12週以上の食事・運動療法が無効でＡＬＴ　３１ＩＵ／Ｌ以上のＮＡＦＬＤの被験者（１６名）にグルタチオン（興人ライフサイエンス社製）を１日あたり３００ｍｇ経口投与した。グルタチオン投与開始前と１６週投与後に肝臓生検査し、４週毎に血液検査を行った。表１に結果を示す。
Example 1
(Effectiveness evaluation for NASH / NAFLD)
Glutathione (manufactured by Kojin Life Science Co., Ltd.) was orally administered to 300 mg / day to NAFLD subjects (16 persons) who had no diet / exercise therapy for 12 weeks or more and who had an ALT of 31 IU / L or more. Liver biopsy was performed before the start of glutathione administration and after 16 weeks of administration, and blood tests were performed every 4 weeks. Table 1 shows the results.
本願発明の効果がある被験者（症例ＩＤ１から９）と効果がない被験者（症例ＩＤ１０から１６）で本発明の効果を表２にまとめた。 The effects of the present invention are summarized in Table 2 for subjects having the effects of the present invention (case IDs 1 to 9) and subjects having no effects (case IDs 10 to 16).
Figure JPOXMLDOC01-appb-T000001
Figure JPOXMLDOC01-appb-I000002
Figure JPOXMLDOC01-appb-T000001
Figure JPOXMLDOC01-appb-I000002
表１中、症例ＩＤ１～９は、投与開始前のＡＬＴが、投与後に２０％以上改善した群である。なお、測定のばらつきがあるため、本発明の投与後開始後、投与前（０ｗｋ）のＡＬＴ値よりも２０％以上改善した週がある場合に効果ありとしている。次に、効果のあった群と効果がなかった被験者とで本発明の投与前の各種検査データを比較した結果を表２に示す。 In Table 1, case IDs 1 to 9 are groups in which ALT before the start of administration improved by 20% or more after administration. Since there are variations in measurement, it is effective when there is a week that is improved by 20% or more from the ALT value before administration (0 wk) after the start of administration of the present invention. Next, Table 2 shows the results of comparison of various test data before administration of the present invention between the group having the effect and the subject having no effect.
Figure JPOXMLDOC01-appb-T000003
Figure JPOXMLDOC01-appb-T000003
（実施例２）
 マウスを用いて、さらに本発明の効果を確認した。
 マウス（Ｃ５７／Ｂ６Ｊ、８週齢　オス）を４群（各５匹）に分け、第１群（ＤＢ）は、通常食（Ｃｅｒｔｉｆｉｅｄ　Ｄｉｅｔ　「ＭＦ」　オリエンタル酵母社製）を自由に摂食させた。第２群（ＨＦＤ）は、高脂肪食（Ｈｉｇｈ　Ｆａｔ　Ｄｉｅｔ　３２、日本クレア製）を自由に摂食させ、水のみを自由に与えた。第３群（ＨＦＤ６）は、高脂肪食（Ｈｉｇｈ　Ｆａｔ　Ｄｉｅｔ　３２、日本クレア製）を自由に摂食させ、グルタチオンを６ｍｇ／ｋｇ／ｄａｙ摂取できるよう、水にグルタチオンを混合させた。第４群（ＨＦＤ６０）は、高脂肪食（Ｈｉｇｈ　Ｆａｔ　Ｄｉｅｔ　３２、日本クレア製）を自由に摂食させ、グルタチオンを６０ｍｇ／ｋｇ／ｄａｙ摂取できるよう、水にグルタチオンを混合させた。
　２０週齢時に、体重、肝臓重量、血清アスパラギン酸アミノトランスフェラーゼ（ＡＳＴ）、 アラニンアミノトランスフェラーゼ（ＡＬＴ）、血清トリグリセリド（ＴＧ）、遊離脂肪酸値（FFA）、総コレステロール値（Ｔ－ｃｈｏ)を測定した。 (Example 2)
The effect of the present invention was further confirmed using a mouse.
Mice (C57 / B6J, 8-week-old male) were divided into 4 groups (5 each), and the first group (DB) was allowed to freely eat a normal diet (Certified Diet “MF” manufactured by Oriental Yeast Co., Ltd.). . The second group (HFD) freely fed a high fat diet (High Fat Diet 32, manufactured by CLEA Japan) and was given water only. The third group (HFD6) was allowed to freely feed a high fat diet (High Fat Diet 32, manufactured by CLEA Japan) and mixed glutathione with water so that 6 mg / kg / day of glutathione could be ingested. The fourth group (HFD60) was allowed to freely feed a high fat diet (High Fat Diet 32, manufactured by CLEA Japan), and mixed with glutathione in water so that 60 mg / kg / day of glutathione could be ingested.
At 20 weeks of age, body weight, liver weight, serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), serum triglyceride (TG), free fatty acid level (FFA), and total cholesterol level (T-cho) were measured. .
 体重と肝臓重量の結果を図１と図２に示す。さらに、餌、水分消費量についても図３に示す。餌、水分消費量は、すべての群で有意な差はなかった。本発明投与群では、体重の減少が見られた。さらに図４に示したように、肝臓重量が、本発明の濃度依存的に減少し、体重比においても減少が見られた。これは、高脂肪食による肝臓へ脂肪が蓄積することが抑制されたことが分かった。 The results of rabbit body weight and liver weight are shown in FIG. 1 and FIG. Furthermore, the bait and water consumption are also shown in FIG. There was no significant difference in food and water consumption among all groups. In the administration group of the present invention, weight loss was observed. Furthermore, as shown in FIG. 4, the liver weight decreased depending on the concentration of the present invention, and the body weight ratio also decreased. It was found that the accumulation of fat in the liver due to the high fat diet was suppressed.
 図５に血清ＡＳＴ及びＡＬＴ、図６にＴＧ（中性脂肪酸値）、ＦＦＡ（遊離脂肪酸値）及びＴ－ｃｈｏ（総コレステロール値）の結果を示す。ＨＦＤ群と比較し、ＨＦＤ６群、ＨＦＤ６０群は、有意に低下していた。またＨＤＦ６群とＨＦＤ６０群を比較すると、本発明品の濃度依存的に低下がみられた。 FIG. 5 shows the results of serum AST and ALT, and FIG. 6 shows the results of TG (neutral fatty acid level), FFA (free fatty acid level), and T-cho (total cholesterol level). Compared with the HFD group, the HFD6 group and the HFD60 group were significantly reduced. In addition, when the HDF6 group and the HFD60 group were compared, a decrease was observed depending on the concentration of the product of the present invention.
 マウスにおいても、本発明品の投与により、非アルコール性脂肪肝への有効性が確認された。実施例２のマウスモデルでは、高脂肪食摂取による肝臓への影響のみを確認できるモデルであるため、本発明品の実施例１での効果を観察できた。 In sputum mice, the effectiveness of the product of the present invention on non-alcoholic fatty liver was also confirmed. Since the mouse model of Example 2 is a model that can confirm only the influence on the liver due to the intake of a high fat diet, the effect of Example 1 of the product of the present invention was observed.
 本実施例の結果から、代謝異常（高血圧、糖尿、脂質異常）の異常が軽い若しくはない場合、既往歴若しくは内服歴のない場合、肝硬度が低い場合（エラストグラフィー又はＴｙｐｅＩＶコラーゲン）の数値により判断）、又は、糖尿病を併発していない場合（糖化ヘモグロビンの割合により判断）の非アルコール性脂肪性肝疾患の改善に本願発明は特に有効である。 From the results of this example, judgment is made based on numerical values when abnormalities of metabolic abnormalities (hypertension, diabetes, lipid abnormalities) are light or absent, when there is no past history or internal history, or when liver hardness is low (elastography or Type IV collagen). ) Or the present invention is particularly effective in improving nonalcoholic fatty liver disease when diabetes is not complicated (determined by the proportion of glycated hemoglobin).
体重の経過Weight course ２０週齢時の体重Weight at the age of 20 weeks 水分、餌の摂取量Water and food intake 肝臓重量、肝臓重量／体重比Liver weight, liver weight / body weight ratio 血清ＡＳＴ、血清ＡＬＴSerum AST, Serum ALT ＴＧ（中性脂肪酸値）、ＦＦＡ（遊離脂肪酸値）、Ｔ－ｃｈｏ（総コレステロール値）TG (neutral fatty acid level), FFA (free fatty acid level), T-cho (total cholesterol level)

Claims (6)

  1. グルタチオンを有効成分として含有する非アルコール性脂肪肝疾患の改善用組成物。 A composition for improving nonalcoholic fatty liver disease containing glutathione as an active ingredient.
  2. グルタチオンを有効成分として含有する非アルコール性脂肪肝疾患の予防用組成物。 A composition for prevention of non-alcoholic fatty liver disease containing glutathione as an active ingredient.
  3. 非アルコール性脂肪肝疾患が、非アルコール性脂肪肝のみを発症している疾患である請求項１又は２の組成物。 The composition according to claim 1 or 2, wherein the non-alcoholic fatty liver disease is a disease that develops only non-alcoholic fatty liver disease.
  4. 非アルコール性脂肪肝疾患が、糖尿病を併発していない疾患である請求項１又は２の組成物。 The composition according to claim 1 or 2, wherein the non-alcoholic fatty liver disease is a disease not accompanied by diabetes.
  5. 非アルコール性脂肪肝疾患が、肝硬度の低い疾患である請求項１又は２の組成物。 The composition according to claim 1 or 2, wherein the non-alcoholic fatty liver disease is a disease with low liver hardness.
  6. 非アルコール性脂肪肝疾患が、糖化ヘモグロビン（ＨｂＡ１ｃ）が６．５％以下の疾患である請求項１又は２の組成物。 The composition according to claim 1 or 2, wherein the non-alcoholic fatty liver disease is a disease in which glycated hemoglobin (HbA1c) is 6.5% or less.
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